%0 Journal Article
%A Rifat, Ali
%A Ossola, Bernardino
%A Bürli, Roland W
%A Dawson, Lee A
%A Brice, Nicola L
%A Rowland, Anna
%A Lizio, Marina
%A Xu, Xiao
%A Page, Keith
%A Fidzinski, Pawel
%A Onken, Julia
%A Holtkamp, Martin
%A Heppner, Frank L
%A Geiger, Jörg R P
%A Madry, Christian
%T Differential contribution of THIK-1 K+ channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia.
%J Journal of neuroinflammation
%V 21
%N 1
%@ 1742-2094
%C London
%I BioMed Central
%M DZNE-2024-00222
%P 58
%D 2024
%X Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation.
%K Humans
%K Microglia: metabolism
%K NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
%K Neuroinflammatory Diseases
%K Ion Channels: metabolism
%K Adenosine Triphosphate: pharmacology
%K Adenosine Triphosphate: metabolism
%K Receptors, Purinergic P2X7: metabolism
%K NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
%K Human brain (Other)
%K Ion channels (Other)
%K Microglia (Other)
%K Neocortex (Other)
%K Neuroinflammation (Other)
%K Pharmacology (Other)
%K Purinergic signalling (Other)
%K Ion Channels (NLM Chemicals)
%K Adenosine Triphosphate (NLM Chemicals)
%K Receptors, Purinergic P2X7 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC10895799
%$ pmid:38409076
%R 10.1186/s12974-024-03042-6
%U https://pub.dzne.de/record/268470